Individual use of self-medication and other remedies in COVID-19 outpatients in Western-Pomerania

We analyzed data from positively tested COVID-19 outpatients to describe self-medication with OTC drugs and use of other remedies against symptoms of SARS-CoV-2 infection. We specifically considered their type and frequency, as well as associations with patient characteristics, and reasons for use. Data were collected between May 1, 2020 and February 22, 2021 with two questionnaires in an observational cohort study with PCR-confirmed SARS-CoV-2-positive adult outpatients in the district of Western Pomerania in Germany. 523 out of 710 outpatients (74%; 340 women and 183 men) reported using drugs and other remedies to relieve COVID-19-symptoms. Overall, participants reported utilization of 1282 finished dosage products or remedies, including 213 different ingredients. In the population of 710 outpatients, utilization of ibuprofen (26%), acetaminophen (21%), metamizole (14%), and acetylsalicylic acid (10%) was most commonly reported. Phytopharmaceuticals, herbal and animal products as well as vitamins and minerals were also frequently reported. Among the 523 participants who used drugs and other remedies, most commonly mentioned reasons for use were headache (40%), other kinds of pain (e.g. myalgia; 37%), fever (24%) and cough (16%). Our analysis showed that a majority of the participants tried to alleviate COVID-19-symptoms using drugs and other remedies. Especially analgesic and antipyretic agents, followed by herbal medicines, were used very frequently. Trial registration: German Register for Clinical Studies DRKS00021672, first registration on December 1st, 2020.

were reported more frequently in men than women.Table 1 summarizes the most important characteristics of the study population.Part of these data have already been reported in the original publication of the course and symptoms of COVID-19 in this particular outpatient population 11 .
We asked the participants to complete a symptom diary covering 16 symptoms and a period of 25 days (see 11 for details).Seven hundred participants delivered diaries, most commonly reported symptoms were fatigue (79.6%), cough (productive and dry cough were summarized; 72.3%) and headache (69.6%).Of the participants, 4.9% were asymptomatic and 5.2% (n = 695) required hospitalization.The largest proportion of participants reported a duration of symptoms of 25 days (30.2%; n = 700).Our population also showed sex-specific differences in the course of COVID-19 disease, with symptoms lasting an average of 17.5 days in women and 13.5 days in men (p < 0.001).Headaches, loss of smell and taste, sore throat or gastrointestinal complaints occurred more frequently in women 11 .

Use of pharmaceutical products and other remedies
Out of 710 study participants, 523 (73.7%) reported usage of drugs and other remedies to treat symptoms due to SARS-CoV-2 infection.Women reported a higher rate than men (80.0% vs. 64.2%,p < 0.001).A total of 1282 finished dosage products and other remedies were reported.The number of products and remedies per participant ranged from one to eleven, with a mean of 2.6 in women and 2.2 in men (n = 523; p = 0.027).In total, we identified 213 different ingredients.Several of the reported products and remedies contained more than one ingredient, adding up to 1453 reported utilizations of these ingredients.Ingredients reported by at least ten participants are shown in Table 2.The largest group (n = 531 reported utilizations) were analgetic, antiphlogistic and antipyretic drugs (e.g.ibuprofen, acetaminophen, metamizole, acetylsalicylic acid).Second, 406 out of 1453 reported utilizations belonged to phytopharmaceuticals, herbal (e.g.home-grown or self-collected herbs, onion juice or lemon) and animal products (e.g.honey, milk, chicken broth), including products such as teas or self-made home remedies.Vitamins and minerals represented the third largest group (141 out of 1453).Considering the most frequently reported individual ingredients in each of these three classes, 25.5% of the 710 study participants used ibuprofen, 20.6% acetaminophen, 13.7% metamizole and 10.0% acetylsalicylic acid.Furthermore, 4.4% of participants mentioned preparations of eucalyptus, 3.8% thyme, 3.7% lemon and 3.3% primrose.Among vitamins and minerals 6.3% of the participants reported vitamin C, 3.1% vitamin D and 2.7% zinc.Furthermore, many study participants reported drugs against cough or rhinitis, for example with acetylcysteine (4.2%), xylometazoline (4.1%), or containing sodium chloride or sea-salt (3.1%).

Reasons for the use of pharmaceutical products and other remedies
Because study participants reported reasons for using pharmaceutical products and remedies in their own wording, the answers were rather diverse and we summarized them in groups (Table 3).Forty percent of the n = 523 participants utilizing a pharmaceutical product or other remedies mentioned headache, the second most common reason were other types of pain such as myalgia or arthralgia (37.3%).Fever was reported by 23.9%, cough by ) and diarrhea (0.6%), or "strengthening" of the immune system (2.1%) were some of the less frequently reported reasons.

Correlations between pharmaceutical products and remedies and characteristics of the study population
We also analyzed correlations between the utilized number of pharmaceutical products and other remedies to treat the symptoms of SARS-CoV-2 infection and certain characteristics of the study population (age, BMI, number of comorbidities, long-term medication, duration and number of symptoms).A positive linear correlation was only found for the number of days with symptoms (r = 0.425; p < 0.001) and the number of different symptoms (r = 0.470; p < 0.001).Furthermore, participants with certain risk factors for a more severe course of disease (e.g.BMI ≥ 25 kg/m 2 , cardiovascular diseases, hypertension, diabetes mellitus or lung diseases, n = 515) were compared with those without the mentioned risk factors (n = 195).No significant differences were found in the usage of particular active substances or the number of pharmaceutical products and other remedies used between those two groups.

Discussion
In this analysis, we determined the use of drugs and other remedies against symptoms of SARS-CoV-2 infection in outpatients.We assumed that the majority of participants were self-medicating with over-the-counter (OTC) drugs, however, we captured all drugs mentioned, both OTC as well as prescribed drugs.Our results show a hugh variety of utilized drugs and remedies and reasons for their use.Overall, 340 women and 183 men out of 710 outpatients reported using drugs and other remedies to relieve COVID-19-symptoms.We identified 213 different ingredients, and utilization of ibuprofen (26%), acetaminophen (21%), metamizole (14%), and acetylsalicylic acid (10%) was most commonly reported.Phytopharmaceuticals, herbal and animal products as well as vitamins and minerals were also frequently reported.
Except for a minimum age of 18 years and a current positive PCR test, there were no other inclusion or exclusion criteria for the recruitment of study participants.More women than men consented into participation.The proportion of COVID-19 patients with comorbidities (68.9%) in our cohort is slightly higher than in published data for individuals with chronic diseases in Germany, e.g.49.2% in surveys by the Robert Koch Institute 12 .Most comorbidities (e.g.cardiovascular diseases) were more commonly reported by men, similar sex-specific differences are reported in the published data 12,13 .
COVID-19 symptoms were more frequent and longer lasting in women.30.2% of participants reported a symptom duration of 25 days.However, because the questionnaire only included a 25-day symptom diary, longer symptom duration could not be detected with our questionnaire.The prevalence of individual symptoms varies considerably in the published data, possibly because of differences in study designs, symptom descriptions, study populations, utilized therapies, and the respective infection processes at different locations and times of COVID-19 study conduct.
Our results suggest that more women than men (80.0% vs. 64.2%,p < 0.001) tried to alleviate COVID-19-symptoms by using pharmaceutical products and other remedies.Published data for self-medication use in Germany, regardless of a specific disease, show a comparable proportion between men and women 14 .Women also used a greater number of products or remedies against their symptoms.Except the longer average duration of symptoms in women, no reasons for these differences can be deduced from our study results.Published data suggests that contributing factors may be a greater awareness of health and body, a broader knowledge of health issues and a stronger connection to the healthcare system [15][16][17] .Overall, the participants stated a variety of pharmaceutical products and remedies and reasons for use.Especially analgesic and antipyretic agents, followed by phytopharmaceuticals as well as vitamins and minerals, have been used very frequently.In particular, these products and remedies were utilized against general symptoms of respiratory diseases like headache, myalgia, arthralgia, fever and cough which were also frequently mentioned in the symptom diary.Specific symptoms like loss of smell or taste and dyspnea were commonly reported, but rarely were reported as a reason for drug use, probably due to low availability of suitable drugs.The frequency distribution of pharmaceutical products and remedies corresponds approximately to the indication groups of the non-prescription drugs with the highest sales in Germany which include the respiratory system (e.g.remedies against cold), the alimentary system and metabolism (e.g.vitamins and minerals) and the nervous system (e.g.analgesic drugs) 18 .Published data for self-medication use in Germany also show a frequent use of products from these Anatomical-Therapeutic-Chemical-groups 19 .
With regard to frequently reported symptoms such as headache, myalgia, fever or cough, a large frequency of utilization of analgesic, antipyretic and antitussive or expectorant drugs was expected.The most frequently mentioned active ingredient was ibuprofen (25.5%; n = 710), which is the second most prescribed drug in Germany Table 3. Reasons for use of pharmaceutical products or other remedies against SARS-CoV-2-infection. Summarizing terms for reasons to apply pharmaceutical products and other remedies which study participants reported at least once.Values are shown as numbers (%).p-values describe group comparisons between men and women using the Pearson chi-square test..Originally, the questionnaires for drug use were also developed to prove the public assumption at that early stage of the pandemia that ibuprofen and ACE-inhibitors carried a risk for more severe courses of the disease.As described in the original publication, we could exclude these drugs as risk factors for higher infection rates or as cause for a more severe course 11 .Several further studies were published which could not prove an assumed increased risk, for example due to ibuprofen 21 .Metamizole (13.7%) was also frequently used.Metamizole is only available on prescription in Germany and has a restricted therapeutic indication, however it was the most frequently prescribed drug in 2020 in Germany 20 .Thus, the large number of patients who took metamizole in our cohort is on first sight not surprising, but in terms of drug therapy safety, the finding is alarming, because many of these patients were not under regular medical control.
The second most frequently prescribed group of active ingredients in our study were phytopharmaceuticals, herbal and animal products.They include many different drugs used against colds and flu, cough, sore throat or sinusitis.Eucalyptus, thyme and primrose were common ingredients.Combination medicines containing several active ingredients were also frequently used here.
In addition, we analyzed correlations between number of reported pharmaceutical products and other remedies and characteristics of our cohort such as age, BMI, comorbidities and course of disease.Only the duration of symptomatic course and the number of different symptoms were moderately correlated with the frequency of usage.
Other studies which determined drug use and self-medication to relieve COVID-19 symptoms are not easily comparable to ours.Several studies conducted in countries other than Germany focused on self-medication during the COVID-19 pandemic, but often without confirmation of the infection.Some studies analyzed selfmedication in the context of COVID-19 prevention [7][8][9][10] .The frequent use of antibiotics, antimalarial drugs (e.g.hydroxychloroquine), and ivermectin for self-medication in these studies is conspicuous.During the initial time of the SARS-CoV-2 pandemic, the knowledge about the course of the disease and treatment possibilities was very limited and characterized by uncertainty and missinformation.In our study, antimalarial and anthelminthic drugs were not, and antibiotics were only rarely mentioned.Comparable to published data, we found a frequent use of vitamins and minerals, phytopharmaceuticals and analgesic and antipyretic drugs.However, comparisons with other countries, especially non-European Union countries, are difficult, due to different legal requirements, awareness and accessibility of medicines.

Limitations
However, we were limited in analyzing the dosage and course of drug use because of the questionnaire design.The participants were asked to indicate the number of days they utilized each drug, but we could not infer the exact day during the infection, so we were not able to assign a chronological relationship between symptoms course or comedication.Based on the observational cohort study design, no causal relationships could be determined between the course of disease and self-medication.Moreover, neither the efficacy of utilized drugs and remedies, nor participants' satisfaction regarding symptom relieve or duration of infection could be determined.A huge number of different pharmaceutical products and remedies were used, so the frequency of many products and remedies was too small to determine causality or significance with regard to the impact of individual active ingredients.The questionnaires were initially created to collect data on the course of disease and risk factors for hospitalization in outpatients for the COVER study 11 .Due to the extensive number of questions in the questionnaires, to further analyze aspects such as self-medication seemed appropriate.However, this also resulted in some limitations for the evaluation as described.Other aspects are for example possible selection bias with regard to comorbidities, risk factors or symptomatic course of disease.Also, there were no restrictions regarding the description of drugs and other remedies or the reasons for use, it is difficult to summarize them.As this is an observational study based on questionnaires, there was no randomization or intervention.Therefore, it is not possible to establish direct causal relationships between individual parameters.

Conclusion
The main focus of our analysis was to determine and describe drugs and remedies taken to alleviate the symptoms of a confirmed SARS-CoV-2 infection in German outpatients.Almost three quarters of participants reported the utilization of a wide variety of drugs and remedies.We were able to show that the majority used active ingredients which are also typically used to alleviate colds, flu or other respiratory infections.Further studies to examine a possible causal relationship between OTC drugs and course of COVID-19 disease would be useful for medical and pharmaceutical advice.

Table 1 .
11aracteristics of the study population (taken in part from11).Values are shown as numbers (%), age and BMI as mean (minimum and maximum value).p-values describe group comparisons between men and women (Pearson chi-square test for frequencies; t-test for independent samples for age and BMI).BMI body mass index.*n = 705 (283 men; 422 women).**n = 699 (280 men; 419 women).Bold: p ≤ 0.05.